Clotting of blood is an essential part of the hemostatic response and depends on a very delicate balance between a number of interrelated factors. Blood clotting consists of a series of biochemical reactions, commonly referred to as the clotting cascade. Each product of these reactions is an enzyme which catalyzes the next reaction in the sequence.
The clotting cascade is triggered by the activation of Hageman factor, also known as clotting factor XII. Activation of factor XII occurs when it comes into contact with negatively charged surfaces such as those that appear on exposed collagen fibers and on reacting platelet membranes. These conditions occur when blood vessels are punctured or attacked. Active Hageman factor (XIIa) then converts inactive plasma thromboplastin antecedent ("PTA") (factor XI) into its active form (XIa). XIa then convents plasma thromboplastin component ("PTC") (IX) to active plasma thromboplastin component (IXa), which, in turn converts Stuart-Prower factor (X) to its active form (Xa). Active Stuart-Prower factor converts the inactive form of prothrombin to the active enzyme, thrombin, which rapidly catalyzes the conversion of fibrinogen to fibrin which polymerizes to form a network of insoluble threads at the site of the injury.
Clotting (thrombosis) is the ultimate mechanism responsible for most blood vessel blockage, which in turn results in interrupted blood flow to the organ that the blood vessel perfuses. Strokes, heart attacks, and gangrene result from clotting on the arterial side of the circulation. Clotting on the venous side of the circulation is called phlebothrombosis and is also responsible for a number of substantial problems, such as thrombophlebitis, venous insufficiency, venous ulceration, and pulmonary embolism. (The latter can occur when a clot in an extremity dislodges and travels to the lung).
Clotting is also a major concern in surgical procedures which involve the grafting of blood vessels. Such clotting often occurs in the immediate post-operative period, within the first several hours after successful surgery has apparently been accomplished. During this time the endothelium (the inner most layer of blood vessel and the layer which is in contact with the blood), which has been disrupted or damaged by the surgical procedure, releases a variety of compounds, including cytokines, and activated white blood cells to cause tissue factor expression that stimulates clotting. Two common surgical procedures which can result in endothelium damage are coronary artery (major blood vessels feeding the heart musculature) bypass grafting surgery and creation of arteriovenous fistulas either by direct artery to vein anastomosis or by insertion of a graft of man made material (such as GORETEX.TM., a highly microporous poly tetrafluoroethylene, available from W.L. Gore and Associates, Inc., Newark, Del.) between an artery and a vein. More than 300,000 heart bypass procedures are performed in the United States each year to re-establish circulation to the heart. Creation of either an arteriovenous fistula or graft is an essential part of the preparation needed for the approximately 150,000 patients who are receiving regular hemodialysis to treat their end stage kidney disease. Endothelium damage and, consequently, the danger of post-procedure clotting, can also result from non-surgical procedures, such as angioplasty. Each year, more than 300,000 angioplasty procedures are performed to dilate narrowed segments of the coronary arteries. Unfortunately, because of the endothelial damage that can result from these procedures, recurrence of the narrowing (restenosis) or complete occlusion of the blood vessel can occur. Indeed the rate of restenosis of the coronary blood vessel following this balloon angioplasty is 40% within the first six months following the procedure. There are also an ever increasing number of angioplasty procedures being employed to dilate arteries that perfuse peripheral vascular beds, such as those of the legs, and restenosis remains a problem with these vessels as well.
To prevent the occurrence or reoccurrence of clotting, patients are frequently given anticoagulants after operations undertaken to repair blood vessels. Anticoagulants are also commonly used post-surgery to prevent venous clotting in patients with decreased motion. They are also used to prevent stroke and heart attack in patients who are proven to have, or suspected of having, abnormal blood vessels.
A variety of agents are presently used to control clotting. Urokinase, streptokinase, and (recombinant) tissue plasminogen activator ("rt-PA") are chemicals that cause clots to dissolve. These clot dissolving agents are generally used in emergency situations, such as a heart attack, where they lyse clots which have formed in the coronary arteries. Typically, these agents are injected into the blood stream or organ close to where the clot is suspected of having been formed. Although they will interrupt clotting anywhere that they reach an effective concentration in the blood stream, these agents are not used as prophylaxis against additional clotting because they have a high side-effect profile and, secondarily, because they are moderately (Streptokinase) or very (rt-PA) expensive. A recent study which evaluated the combined effects of angioplasty and thrombolytics in the treatment of arterial occlusive disease of peripheral vessels revealed a greater than 40% rate of bleeding (hemorrhagic) complications. Both urokinase and rt-PA also must be given intravenously posing another limitation on treatment. Further, patients may develop antibodies to these compounds which can restrict their repeated use.
Heparin and coumadin are two chemicals commonly used for prophylaxis to prevent clot formation. Heparin consists of sulfated simple chain polysaccharides of variable length and inhibits clotting by combining with antithrombin III, forming a complex capable of directly inhibiting the generation of thrombin as well as accelerating thrombin's decay. It is usually administered intravenously in a hospital setting. Even when administered subcutaneously, heparin is seldom used outside the hospital setting because changes in dose are frequently necessary (although low molecular weight heparin may be useful when administered subcutaneously to outpatients). Coumadin inhibits certain liver-made factors which are critical to the clotting process. Coumadin is relatively inexpensive, and is often prescribed as part of a long-term treatment regimen, lasting months or years. It is specifically used for prevention of recurrent heart attacks, strokes, thrombosis of artificial heart valves, and in a variety of other clinical circumstances.
Both heparin and coumadin act systemically rather than locally. Because of the systemic nature of treatment using these anticoagulants, careful monitoring of their levels in the blood is required. Anticoagulant levels within the therapeutic range, that is, between excessive anticoagulant (in which case the patient may experience undesirable bleeding elsewhere, such as from a cut, a bruise, or an ulcer) and insufficient anticoagulant, are often difficult to establish and maintain. Furthermore, even when blood levels are within the therapeutic range, there is a substantial increase in the incidence of bleeding. Patients who have an ulcer or other bleeding disorder are especially difficult to treat with these systemic anticoagulants.
Recently, aspirin has found wide use as a clot inhibitor, particularly with respect to clots on the arterial side of circulation. Aspirin inhibits the aggregation of platelets, which is often the first stage in clot development. Aspirin's effect is, therefore, also systemic and, consequently, use of this compound suffers some of the drawbacks associated with coumadin and heparin. In addition, aspirin's effect on platelets is long term, lasting a generation of platelets or about 7-10 days. Consequently, the ability of a patient's blood to coagulate, once impaired by aspirin, cannot be re-established without delay by simply discontinuing use of the aspirin.
It is apparent from the above discussion that a need exists for better ways to prevent clotting.
Ultrasonography is a noninvasive procedure utilizing reflection of high frequency sound waves from organs of the body to derive images. The imaging results from the variable reflection or absorption of wave energy by the different materials from which tissues and organs are comprised. The safety of the procedure is reflected by its extensive use as a tool to monitor the development of the fetus during gestation.
Ultrasound has also been used clinically to measure the flow of blood through blood vessels, as described in U.S. Pat. No. 4,227,407 to Drost. The device described therein measures the flow of fluid through a conduit by comparing the time of travel of ultrasound from an upstream ultrasound source to a downstream ultrasound detector with the time of travel from a downstream ultrasound source to an upstream ultrasound detector. The device and method are applicable generally to any fluid in any conduit and, specifically, to the measurement of blood flow through a blood vessel.
Ultrasound has also found clinical application in mechanically disrupting masses, such as gall stones and kidney stones, as well as in diathermy. Ultrasound is also being explored in the treatment of thrombotic vascular disease using two approaches: non-enzymatic and enzymatic (Siegel et al., "Clinical demonstration that catheter-delivered ultrasound energy reverses arterial vasoconstriction," J. Am. Coll. Cardiol. 20:732-735 (1992) and Francis et al., "Enhancement of fibrinolysis in vitro by ultrasound," J. Clin. Invest. 90:2063-2068 (1992)). Non-enzymatic treatment utilizes low-frequency (20-25 kHz), high-power (ca. 20 W) ultrasound to mechanically disrupt clots and atherosclerotic plaque, the debris from which is trapped distally (Ernst et al., "Ability of high-intensity ultrasound to ablate human atherosclerotic plaques and minimize debris size," Am. J. Cardiol. 68:242-246 (1991)). Complications arising from the intensity of the ultrasound used include heating of the blood, perforation of the vessel wall, and vessel wall damage (Ernst et al., "Ability of high-intensity ultrasound to ablate human atherosclerotic plaques and minimize debris size," Am. J. Cardiol. 68:242-246 (1991) and Gillebert et al., "Intracavitary ultrasound impairs left ventricular performance: presumed role of endocardial endothelium," Am. J. Physiol. 263:H857-H865 (1992)). Low-intensity, high-frequency ultrasound has been found to accelerate fibrinolysis catalyzed by enzymatic clot dissolving agents, such as rt-PA and Urokinase. By using such agents in combination with ultrasound, the intensity of the ultrasound necessary to dissolve clots is reduced to 1-3 W/cm.sup.2, thereby avoiding the damaging effects of non-enzymatic ultrasound treatment.
Thus, the currently published information regarding the possible application of ultrasound to treat clotting disorders suggests that this modality is useful only for dissolution of established blood clots. Further, the energy levels of the sound waves that are effective to dissolve established clots can damage the blood vessel walls where the clots have formed or lodged. Treatment with lower levels of ultrasound energy is possible, but only when used to supplement chemical anticoagulants which may have systemic effects.
For the foregoing reasons, there remains a need for a method for preventing in vivo clot formation without the deleterious side effects or systemic impact of the chemicals presently used. Specifically, there remains a need for a method of preventing clot formation in a selected segment of a blood vessel.